Compounds for Treatment of Complement Mediated Disorders

Abstract

Compounds, methods of use, and processes for making inhibitors of complement factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and essential point in the alternative complement pathway, and reduce factor D's ability to modulate the classical and lectin complement pathways. The inhibitors of factor D described herein are capable of reducing the excessive activation of complement, which has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 14 / 631,828, filed Feb. 25, 2015, which claims the benefit of provisional U.S. Application No. 61 / 944,189 filed Feb. 25, 2014, provisional U.S. Application No. 62 / 022,916 filed Jul. 10, 2014, and provisional U.S. Application 62 / 046,783 filed Sep. 5, 2014. The entirety of each of these applications is hereby incorporated by reference for all purposes.BACKGROUND[0002]The complement system is a part of the innate immune system which does not adapt to changes over the course of the host's life, but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens. This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction. Over thirty proteins and protein fragments make up the complement system. These proteins act throu...

AI Technical Summary

Benefits of technology

[0020]In one embodiment, the disorder is associated with the alternative complement cascade pathway. In yet another embodiment, the disorder is associated with the complement classical pathway. In a further embodiment, the disorder is associated with the complement lectin pathway. The factor D inhibitors provided herein can thus dampen or inhibit detrimental complement activity in a host, by administration of an effective amount in a suitable manner to a host in need thereof.

Problems solved by technology

Age-related macular degeneration (AMD) is a leading cause of vision loss in industrialized countries.

Individuals with mutations in the gene encoding complement factor H have a fivefold increased risk of macular degeneration and individuals with mutations in other complement factor genes also have an increased risk of AMD.

Without adequate functioning factor H, the alternative pathway of the complement cascade is overly activated leading to cellular damage.

However, many of the patients treated with eculizumab remain anemic, and many patients continue to require blood transfusions.

In addition, treatment with eculizumab requires life-long intravenous injections.

While initial attempts have been made to develop inhibitors of factor D, there are currently no small molecule factor D inhibitors in clinical trials.

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